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The consensus panel 2 (CP2) of the 11th International Workshop on Waldenström's macroglobulinemia (IWWM-11) has reviewed and incorporated current data to update the recommendations for treatment approaches in patients with relapsed or refractory WM (RRWM). The key recommendations from IWWM-11 CP2 include: (1) Chemoimmunotherapy (CIT) and/or a covalent Bruton tyrosine kinase (cBTKi) strategies are important options; their use should reflect the prior upfront strategy and are subject to their availability. (2) In selecting treatment, biological age, co-morbidities and fitness are important; nature of relapse, disease phenotype and WM-related complications, patient preferences and hematopoietic reserve are also critical factors while the composition of the BM disease and mutational status (MYD88, CXCR4, TP53) should also be noted. (3) The trigger for initiating treatment in RRWM should utilize knowledge of patients’ prior disease characteristics to avoid unnecessary delays. (4) Risk factors for cBTKi related toxicities (cardiovascular dysfunction, bleeding risk and concurrent medication) should be addressed when choosing cBTKi. Mutational status (MYD88, CXCR4) may influence the cBTKi efficacy, and the role of TP53 disruptions requires further study) in the event of cBTKi failure dose intensity could be up titrated subject to toxicities. Options after BTKi failure include CIT with a non-cross-reactive regimen to one previously used CIT, addition of anti-CD20 antibody to BTKi, switching to a newer cBTKi or non-covalent BTKi, proteasome inhibitors, BCL-2 inhibitors, and new anti-CD20 combinations are additional options. Clinical trial participation should be encouraged for all patients with RRWM.

We evaluated the impact on survival of antithymocyte globulin conditioning (TLI-ATG) with radiation (RT) boost to high risk or residual disease before allogeneic hematopoietic cell transplant (allo-HCT) for adults with lymphoma (excluding mycosis fungoides and low-grade NHL other than SLL/CLL). Of 251 evaluable patients, 36 received an RT boost within 3 months of allo-HCT at our institution from 2001 to 2016. At the time of TLI-ATG, patients who received boost vs no boost had a lower rate of CR (11% vs 47%, p = 0.0003), higher rates of bulky disease (22% vs 4%, p < 0.0001), extranodal disease (39% vs 5%, p < 0.0001), and positive PET (75% vs 28%, p < 0.00001). In the boost group, the median (range) largest axial lesion diameter was 5.2 cm (1.8-22.3). Median follow-up was 50.2 months (range: 1-196). There was no significant difference in OS, time to recurrence, or time to graft failure with vs without boost. A trend toward higher percent donor CD3+ chimerism was seen with vs without boost (p = 0.0819). The worst boost-related toxicity was grade 2 dermatitis. RT boost may help successfully mitigate the risk of high risk or clinically evident residual disease in adults with lymphoma undergoing allo-HCT.

Introduction: Mature T and NK-cell lymphomas represent a heterogeneous group of lymphoid disorders (29 subtypes according to the 2016 WHO classification) arising from mature T cells of post-thymic origin with different morphological characteristics, phenotypes, and clinical presentation. Following the success of the T Cell Project (TCP), which allowed the analysis of more than 1,500 cases of peripheral T-Cell lymphomas (PTCLs) collected prospectively in 18 Countries, in 2018 the TCP 2.0 was launched. Here we report the global distribution of PTCLs, from the cases registered so far based on the locally established histological diagnosis. Methods: The TCP2.0 (ClinicalTrials.gov Identifier: NCT03964480) is a prospective, international, observational study which adapts to changes made in the new WHO classification. Results: Since the beginning of the study (October 2018), 648 patients with newly diagnosed PTCL were registered by 75 active centers across 14 countries. Of these data, 594 patients have been validated by the centralized trial office. Overall, PTCL-NOS, Anaplastic large cell lymphoma (ALCL) ALK-negative, and Angioimmunoblastic T-cell lymphoma (AITL), represent the most frequent subtypes, representing 31.3%, 18,9% and 13,5% of cases, respectively. As reported in Table 1, PTCL-NOS represents the most frequent subtype worldwide, whereas Adult T-cell leukemia/lymphoma was more frequent in Brazil, AITL and ALCL ALK-negative in Australia/ India, and ALCL ALK-positive in North America and Europe. Extranodal NK/T-cell lymphoma, nasal type was relatively frequent in Brazil and quite rare in the other Latin America Countries. Finally, many sub-types represent less than 5% of cases in all geographic areas. Conclusions: The TCP2.0 continues to recruit very well, despite the difficulties linked to the COVID-19 pandemic, and may represent a useful resource for the prospective study of this group of rare lymphomas.

International audience; The first European Rhinology Research Forum organized by the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) was held in the Royal Academy of Medicine in Brussels on 17th and 18th November 2016, in collaboration with the European Rhinologic Society (ERS) and the Global Allergy and Asthma European Network (GA2LEN). One hundred and thirty participants (medical doctors from different specialties, researchers, as well as patients and industry representatives) from 27 countries took part in the multiple perspective discussions including brainstorming sessions on care pathways and research needs in rhinitis and rhinosinusitis. The debates started with an overview of the current state of the art, including weaknesses and strengths of the current practices, followed by the identification of essential research needs, thoroughly integrated in the context of Precision Medicine (PM), with personalized care, prediction of success of treatment, participation of the patient and prevention of disease as key principles for improving current clinical practices. This report provides a concise summary of the outcomes of the brainstorming sessions of the European Rhinology Research Forum 2016.

Shale Oil Exploration from Paleocene-early Eocene Sequence in Cambay Rift Basin, India

We report experimental results on a megawatt power level, 140-GHz coaxial gyrotron oscillator. The gyrotron has an inverted magnetron injection gun (IMIG) designed for operation at up to 95 kV and 88 A. The IMIG has an inner grounded anode which extends from the center of the gun down through the entire length of the tube including the cavity and collector. The IMIG was tested at up to 105 kV and 93 A in 3 /spl mu/s pulses, achieving an electron beam power of 10 MW. The output power from the coaxial gyrotron cavity was transported to an internal mode converter and a single mirror that coupled the power out transversely from the tube axis. A maximum output power of up to 1 MW was obtained in the TE/sub 27,11/ mode at 142 GHz at an efficiency of 16%, about one half of the design efficiency. The reduced efficiency was attributed to nonuniformity of the cathode emission and the sensitivity to the relative alignment of the electron gun, coaxial insert, and cavity. The cathode emission over the azimuthal angle was measured for two cathodes and was shown to be nonuniform due to both temperature and emitter work function nonuniformity. The gyrotron was also tested in two alternate configurations: 1) with the internal mode converter removed (axial output), and 2) with both the internal converter and the coaxial insert removed (empty cavity). In operation in the empty cavity configuration, which is equivalent to a conventional gyrotron oscillator, output power of up to 0.9 MW was observed.

We report experimental results of the operation of two ferroelectric cathodes of relatively large size. The first cathode had a diameter of 10.2 cm and was built in the Pierce cathode geometry by Integrated Applied Physics (IAP). It achieved emission currents of up to 1.2 kA (15.3 A/cm/sup 2/) at voltages up to 100 kV, in 150 ns pulses. The second cathode had an annular shape with a diameter of 11.4 cm and a width of 0.25 cm. It was built at the Massachusetts Institute of Technology to produce an annular electron beam for use in a Gyrotron microwave source. It operated at currents of up to 10 A (1.1 A/cm/sup 2/) at 8 kV, in 5 /spl mu/s pulses. Detailed operating characteristics for each of these electron sources are reported. These results indicate that ferroelectric cathodes can be used to produce electron beams of large area and size, with high total operating current and pulse lengths of several microseconds. These sources should be suitable for use in future microwave generation experiments.

A new high‐current density electron source is described. The source consists of a polarized ferroelectric ceramic disk with silver electrodes coated on both faces. The front electrode consists of a periodic silver grid alternating with exposed ceramic. A rapid change in the polarization state of the ceramic results in the emission of a high‐density electron cloud into a 1–10‐mm accelerating diode gap. The anode potential is maintained by a charged transmission line. Some of the emitted electrons traverse the gap and an electron current flows. The emitted electron current has been measured as a function of the gap spacing and the anode potential. Current densities in excess of 70 A/cm2 have been measured. The current is found to vary linearly with the anode voltage for gaps ≤10 mm, and typically exceeds the Child–Langmuir current density by at least two orders of magnitude. The experimental data is compared with predictions from a model in which the electrons emitted from the ferroelectric reflex in the di...

Summary Background: Castleman's disease or angiofollicular lymph node hyperplasia is a rare entity with a localized/unicentric or a generalized/multicentric presentation. Whilie surgery is curable for most localized presentations, there is limited information regarding the optimal management of the multicentric type. The latter type is associated with a poor prognoses and can be associated with the development of lymphoma and infections. Patients and methods: In this report we describe a case of multicentric Castleman's disease who failed steroids and chemotherapy and developed a follicular mixed lymphoma. He was treated with high-dose chemotherapy with autologous stemcell support and remains disease at four years of follow-up. Conclusions: A long-term durable remission may be possible with high dose chemotherapy with stem-cell support. This treatment modality should be considered an option in the management of multicentric Castleman's disease.

Summary form only given, as follows. The gyrotron is under development as a high power source for plasma heating at electron cyclotron resonance. For heating large scale plasmas, such as the DIII-D machine at General Atomics, it is advantageous to have high unit power heating sources to reduce the cost and complexity of the system. We will present preliminary designs of 1.5 and 2 MW gyrotrons at a frequency of 110 GHz. The gyrotron designs are based on previous successful results at the 1 MW level at frequencies from 110 to 170 GHz. The baseline design is for a TE/sub 28,8/ mode cavity with an electron beam of 80 to 110 kV and a current of up to 80 A. The expected efficiency exceeds 30% but it should increase to over 50% with a depressed collector. The output beam will be a Gaussian TEM/sub 00/ mode in free space. The gyrotron will be investigated experimentally in short pulse operation (/spl sim/3 microseconds) at MIT and, if successful, will be developed in a 10 s pulsed or CW version by industry. There are two competing approaches for the design of multimegawatt gyrotrons: conventional, cylindrical cavity gyrotrons and coaxial cavity gyrotrons. The conventional cavity approach is being considered as an extension of present day gyrotron research at 110 GHz. The coaxial cavity gyrotron is under investigation at MIT with the goal of output powers of 3 MW at 140 GHz. Recent experimental results from the coaxial cavity gyrotron at power levels in excess of 1 MW will be presented.

This paper describes the design of a high speed motion estimator using the 2-D log search algorithm. The architecture consists of 5 simple processing elements (PE) where each PE is capable of computing the sum-of-absolute-difference (SAD) to exploit the parallelism. For each step in the 2-D log search procedure, the 5 SADs of the 5 search points are computed in parallel. The design is implemented using Verilog and synthesized using Synopsys. Such a chip would be able to generate the motion vector for each 16*16 macroblock in 14.58 /spl mu/s for 3-step log search, and 24.30 /spl mu/s for 5-step log search. The architecture is well suited for encoding MPEG2 video up to MP@ML.

Summary form only given. A new theory is proposed to explain emission from a ferroelectric cathode using a non-zero initial (kinetic) energy for the electrons emitted from the cathode. The traditional Child-Langmuir limit on current density has been exceeded by most ferroelectric cathode experiments. Ferroelectric emission is inherently from electrons which have been ejected from a cathode with non-zero initial energy. Thus one can question the applicability of the Child-Langmuir limit (which is derived on the assumption that electrons are emitted from the cathode with no initial energy) to explain ferroelectric emission. The new theory proposed here shows that if initial energy is taken into account then we can justify the higher current densities observed in ferroelectric cathode experiments.

Aim: PTCL comprises a subset of aggressive non-Hodgkin lymphomas. Outcomes of frontline treatment (tx) are poor, with complete remission (CR) rates of 39–53% (Reimer 2009; D'Amore 2012) and 5-yr overall survival (OS) rates of 12–49%, depending on subtype (Vose 2008). Brentuximab vedotin (ADCETRIS®; BV) has shown clinical activity in a phase 1 trial of BV in sequence with CHOP or in combination with CHP (CHOP without vincristine; A + CHP) in pts with newly-diagnosed PTCL (Fanale, ASH 2013). Methods: This phase 1, open-label study assessed the safety and efficacy of BV administered sequentially with standard-dose CHOP or in combination with CHP for the frontline tx of PTCL (ClinicalTrials.gov NCT01309789). ALK+ systemic anaplastic large cell lymphoma (sALCL) pts must have had IPI score ≥2. Combination tx included a cohort to determine the recommended dose of BV in A + CHP to be evaluated in an expansion cohort (6 cycles q3wk). Responders could receive single-agent BV (1.8 mg/kg q3wk) for up to 10 additional cycles. Updated progression-free survival (PFS) and OS data from combination tx is presented. Results: The median age of pts was 56 yrs (range, 21–82; n=26). Diagnoses included sALCL (n = 19; 16 ALK-), peripheral T-cell lymphoma-NOS (n = 2), angioimmunoblastic T-cell lymphoma (n = 2), adult T-cell leukemia/lymphoma (n = 2), and enteropathy-associated T-cell lymphoma (n = 1). The maximum tolerated dose of BV in A + CHP was not exceeded at 1.8 mg/kg IV, based on 1 DLT (Grade 3 rash). 23 of 26 pts completed 6 cycles of A + CHP. Treatment-emergent adverse events (≥40%) included peripheral sensory neuropathy, nausea, fatigue, alopecia, diarrhea, and dyspnea. At the end of combination tx, the objective response rate was 100% and CR rate was 88%. After a median observation time of 27.1 months, the 2-yr PFS and OS rates were 54% (95% CI 32, 71) and 80% (95% CI 59, 91), respectively. The estimated median PFS was not reached. No pts went on to receive a consolidative stem cell transplant. Conclusions: A + CHP delivered durable remissions in newly-diagnosed PTCL pts, with a 2-yr PFS rate of 54%. A phase 3 study comparing A + CHP to CHOP in the frontline tx of PTCL is underway (ClinicalTrials.gov NCT01777152). Disclosure: M.A. Fanale: Acted as a consultant for: Seattle Genetics, Inc. Honoraria provided by: Seattle Genetics, Inc. Travel expenses provided by: Seattle Genetics, Inc. Research funding/grants provided to the authors institution by: Seattle Genetics, Inc.; S.M. Horwitz: Consultant: Celgene, Seattle Genetics, Inc., Janssen, Takeda International Pharmaceuticals International Co. Research funding/grants: Takeda International Pharmaceuticals International Co., Kiowa Kirin, Allos, Celgene, Infinity, Seattle Genetics, Inc.; A. Forero-Torres: Research funding/grants provided to the authors institution by: Seattle Genetics, Inc. Speakers bureau: Seattle Genetics, Inc.; N.L. Bartlett: Acted as a consultant for: Seattle Genetics, Inc. Travel expenses provided by: Seattle Genetics, Inc. Research funding/grants provided to the authors institution by: Seattle Genetics, Inc.; R.H. Advani: Research funding/grants: Seattle Genetics, Inc., Genentech, Takeda Pharmaceuticals International Co., Abbott, Allos, Janssen, Pharmacyclics Consultant: Seattle Genetics, Inc., Genentech, Takeda Pharmaceuticals International Co., Celgene; B. Pro: Acted as a consultant for: Seattle Genetics, Inc. Travel expenses provided by:Seattle Genetics, Inc. Research funding/grants provided to the authors institution by: Seattle Genetics, Inc.; R.W. Chen: Acted as a consultant for:Seattle Genetics, Inc. Travel expenses provided by:Seattle Genetics, Inc. Research funding/grants provided to the authors institution by:Seattle Genetics, Inc. Speakers bureau: Seattle Genetics, Inc.; A. Davies: Acted as a consultant for: Seattle Genetics, Inc. Research funding/grants provided to the authors institution by: Seattle Genetics, Inc. Honoraria provided by: Takeda Pharmaceuticals International Co.; T. Illidge: Acted as a consultant for: Seattle Genetics, Inc. Takeda Pharmaceuticals International Co. Research funding/grants provided to the authors institution by: Seattle Genetics, Inc. Honoraria provided by: Takeda Pharmaceuticals International Co.; D. Huebner: Employment: Takeda Pharmaceuticals International Co. Equity ownership (including stock options): Takeda Pharmaceuticals International Co.; D.A. Kennedy: Employment: Seattle Genetics, Inc. Equity ownership (including stock options): Seattle Genetics, Inc.; A.R. Shustov: Acted as a consultant for: Seattle Genetics, Inc. Research funding/grants provided to the authors institution by: Seattle Genetics, Inc. Honoraria provided by: Seattle Genetics, Inc. Speakers bureau: Seattle Genetics, Inc.

P-glycoprotein is an efflux pump for many drugs including doxorubicin and paclitaxel. This study evaluated the coadministration of these drugs with the P-glycoprotein inhibitor valspodar (PSC 833) with the aim of determining: (a) maximum tolerated doses (MTDs) of doxorubicin followed by paclitaxel (DP); (b) the MTD of DP combined with PSC 833 (DPV), without and with filgrastim (G-CSF); and (c) the pharmacokinetic interactions of PSC 833 with doxorubicin and paclitaxel.For the first cycle, patients received doxorubicin as a 15-min infusion followed by paclitaxel as a 1-h infusion. For the second cycle, patients received reduced doses of DP with PSC 833 at 5 mg/kg p.o., four times a day for 12 doses.Thirty-three patients with various refractory malignancies were enrolled and assessable. The MTD of DP without PSC 833 was 35 mg/m(2) doxorubicin and 150 mg/m(2) paclitaxel. The MTD of DPV without G-CSF was 12.5 mg/m(2) doxorubicin and 70 mg/m(2) paclitaxel. The dose-limiting toxicity for both DP and DPV was neutropenia without thrombocytopenia. With G-CSF, the MTD for DPV was 20 mg/m(2) doxorubicin and 90 mg/m(2) paclitaxel. No grade 4 nonhematological toxicities were observed. Five partial and two minor tumor remissions were observed. Paired pharmacokinetics with and without PSC 833 revealed substantial drug interactions with both doxorubicin and paclitaxel.PSC 833 can be administered safely with doxorubicin and paclitaxel. The pharmacokinetic profiles of these drugs are significantly affected by PSC 833, requiring approximately 60% dose reductions for equivalent degrees of myelosuppression.

The failure of convenional chemotherapy in relapsed or refractory and other poor risk AML patients has been linked to expression of the multidrug resistance gene (mdr 1) product P-glycoprotein (P-gp). PSC 833 is a non-competitive inhibitor of P-gp and has been shown in vitro and in vivo to restore sensitivity of resistant tumor cells to anticancer drugs (ACDs). Induction chemotherapy consisting of cytarabine (C) in combination with PSC 833 and escalating doses of mitoxantrone (M) and etoposide (E) over 5 or 6 days were tested in two phase I/II studies in poor prognosis AML. Overall, 59 patients were evaluated: their age ranged between 18 and 70 years. Fourteen patients had primary refractory disease, 25 had relapsed within 9 months from first complete remission (CR), 5 were in second relapse, 10 had secondary AML, and 4 had relapsed post-bone marrow transplantation. PSC 833 was given as a constant i.v. infusion at a rate of 10 mg/kg/24 h for 5 or 6 days, depending on the duration of chemotherapy. In both studies a loading dose of 2 mg/kg of PSC 833 was given on day 1. In the 5-day regimen, the final study doses of the cytotoxic agents were C 1 g/m2/d, M 4.0 mg/m2/d, and E 40 mg/m2/d. In the 6-day regimen, the final study doses of the cytotoxic agents were C 1 g/m2/d, M 4.5 mg/m2/d and E 30 mg/m2/d. The combined efficacy results of both studies indicate that PSC-MEC is active in all treatment indications, complete remission being achieved in 2/5 (40%) second relapses, 8/25 (32%) early relapses, 3/10 (30%) secondary AML, 3/15 (20%) refractory patients and 1/4 (25%) post-BMT relapses. Based on historical controls, this observed overall CR rate (29%) is higher than expected in this high risk patient population. Our data indicate that, in refractory/relapsed AML patients, PSC-MEC regimens had encouraging antileukemic effects, is well tolerated, and has led to Phase III trials in this setting.

A potential mechanism of chemotherapy resistance in acute myeloid leukemia (AML) is the multidrug resistance (MDR-1) gene product P-glycoprotein (P-gp), which is often overexpressed in myeloblasts from refractory or relapsed AML. In a multicenter phase II clinical trial, 37 patients with these poor risk forms of AML were treated with PSC 833 (Valspodar; Novartis Pharmaceutical Corporation, East Hanover, NJ), a potent inhibitor of the MDR-1 efflux pump, plus mitoxantrone, etoposide, and cytarabine (PSC-MEC). Pharmacokinetic (PK) interactions of etoposide and mitoxantrone with PSC were anticipated, measured in comparison with historical controls without PSC, and showed a 57% decrease in etoposide clearance (P =.001) and a 1.8-fold longer beta half-life for mitoxantrone in plasma (P.05). The doses of mitoxantrone and etoposide were substantially reduced to compensate for these interactions and clinical toxicity and in Cohort II were well tolerated at dose levels of 4 mg/m2 mitoxantrone, 40 mg/m2 etoposide, and 1 g/m2 C daily for 5 days. Overall, postchemotherapy marrow hypoplasia was achieved in 33 patients. Twelve patients (32%) achieved complete remission, four achieved partial remission, and 21 failed therapy. The PK observations correlated with enhanced toxicity. The probability of an infectious early death was 36% (4 of 11) in patients with high PK parameters for either drug versus 5% (1 of 20) in those with lower PK parameters (P =.04). P-gp function was assessed in 19 patients using rhodamine-123 efflux and its inhibition by PSC. The median percentage of blasts expressing P-gp was increased (49%) for leukemic cells with PSC-inhibitable rhodamine efflux compared with 17% in cases lacking PSC-inhibitable efflux (P =.004). PSC-MEC was relatively well tolerated in these patients with poor-risk AML, and had encouraging antileukemic effects. The Eastern Cooperative Oncology Group is currently testing this regimen versus standard MEC chemotherapy in a phase III trial, E2995, in a similar patient population.

The failure of convenional chemotherapy in relapsed or refractory and other poor risk AML patients has been linked to expression of the multidrug resistance gene (mdr1) product P-glycoprotein (P-gp). PSC 833 is a non-competitive inhibitor of P-gp and has been shown in vitro and in vivo to restore sensitivity of resistant tumor cells to anticancer drugs (ACDs). Induction chemotherapy consisting of cytarabine (C) in combination with PSC 833 and escalating doses of mitoxantrone (M) and etoposide (E) over 5 or 6 days were tested in two phase I/II studies in poor prognosis AML. Overall, 59 patients were evaluated: their age ranged between 18 and 70 years. Fourteen patients had primary refractory disease, 25 had relapsed within 9 months from first complete remission (CR), 5 were in second relapse, 10 had secondary AML, and 4 had relapsed post-bone marrow transplantation. PSC 833 was given as a constant i.V. infusion at a rate of 10 mg/kg/24h for 5 or 6 days, depending on the duration of chemotherapy. In both studies a loading dose of 2 mg/kg of PSC 833 was given on day 1. In the 5-day regimen, the final study doses of the cytotoxic agents were C 1 g/m2/d, M 4.0 mg/m2/d, and E 40 mg/m2/d. In the 6-day regimen, the final study doses of the cytotoxic agents were C 1 g/m2/d, M 4.5 mg/m2/d and E 30 mg/m2/d. The combined efficacy results of both studies indicate that PSC-MEC is active in all treatment indications, complete remission being achieved in 2/5 (40%) second relapses, 8/25 (32%) early relapses, 3/10 (30%) secondary AML, 3/15 (20%) refractory patients and 1/4 (25%) post-BMT relapses. Based on historical controls, this observed overall CR rate (29%) is higher than expected in this high risk patient population. Our data indicate that, in refractory/relapsed AML patients, PSC-MEC regimens had encouraging antileukemic effects, is well tolerated, and has led to Phase III trials in this setting.

Dihydroxyacetone kinase (DAK) is essential for methanol assimilation in methylotrophic yeasts. We have cloned the DAK gene from Pichia pastoris by functional complementation of a mutant that was unable to grow on methanol. An open reading frame of 1824 bp was identified that encodes a 65.3 kDa protein with high homology to DAK from Saccharomyces cerevisiae. Although DAK from P. pastoris contained a C-terminal tripeptide, TKL, which we showed can act as a peroxisomal targeting signal when fused to the green fluorescent protein, the enzyme was primarily cytosolic. The TKL tripeptide was not required for the biochemical function of DAK because a deletion construct lacking the DNA encoding this tripeptide was able to complement the P. pastoris dak delta mutant. Peroxisomes, which are essential for growth of P. pastoris on methanol, were present in the dak delta mutant and the import of peroxisomal proteins was not disturbed. The dak delta mutant grew at normal rates on glycerol and oleate media. However, unlike the wild-type cells, the dak delta mutant was unable to grow on methanol as the sole carbon source but was able to grow on dihydroxyacetone at a much slower rate. The metabolic pathway explaining the reduced growth rate of the dak delta mutant on dihydroxyacetone is discussed. The nucleotide sequence reported in this paper has been submitted to GenBank with Accession Number AF019198.

A major reason for failure of conventional treatment in acute myeloid leukemia (AML) is primary or secondary resistance of the leukemic cells to anti-neoplastic drugs. One of these mechanisms is characterized by the multi-drug resistance (MDR) phenotype that results from overexpression of the MDR-1 gene product, p-glycoprotein (P-gp) [1, 2]. P-gp has been linked to a number of adverse prognostic variables including age, CD34 phenotype, cytogenetic pattern or leukemia arising secondary to cytotoxic therapy or antecedent hematological disorders [3,4,5,6]. The MDR phenotype is characterized by lower intracellular drug accumulation [7, 8] and reduced sensitivity to the anthracyclines [5, 6, 9]. Several agents capable of reversing drug resistance in vitro have been used clinically [10, 11, 12]. We report here the preliminary results of a multicenter phase I–II trial evaluating PSC-833, a non-nephrotoxic, non-immuno-suppressive analogue of cyclosporin and an inhibitor of the MDR-1 pump, in combination with Mitoxantrone (M), Etoposide (E), Cytarabine (C) (termed PSC-MEC) for treating a poor prognosis subgroup of patients with AML.

Patients with non-myeloid hematologic malignancies (including Hodgkin's and non-Hodgkin's lymphomas, myeloma and acute lymphoid leukemia) or solid tumors underwent cytoreductive conditioning regimens followed by either autologous bone marrow transplantation (ABMT) (n = 343) or transplantation of peripheral blood stem cells (PBSC) with (n = 44) or without bone marrow (BM) (n = 16). In a randomized double-blind phase III multi-center trial, patients received either granulocyte-macrophage colony-stimulating factor (GM-CSF, 10 micrograms/kg/day) or placebo by daily i.v. infusion beginning 24 h after bone marrow infusion and continuing until the absolute neutrophil count (ANC) had recovered toor = 1000/mm3, or for a maximum of 30 days. Median time to neutrophil recovery was significantly shorter in the GM-CSF group (18 vs 27 days, P0.001), and more GM-CSF patients had neutrophil recovery by day 30 (70 vs 48%). Median duration of hospitalization was significantly shorter in the GM-CSF group (29 vs 32 days, P = 0.02). GM-CSF significantly reduced the median time to neutrophil recovery in patients receiving bone marrow only (19 vs 27 days, P0.001) or PBSC with or without bone marrow (14 vs 21 days, P0.001). The overall incidence of adverse events was comparable in the two groups, although more patients in the GM-CSF group discontinued treatment due to adverse events (17 vs 9%, P0.001). No difference was noted in infection incidence or time to platelet independence. GM-CSF had no negative impact on time to relapse or long-term survival. These data indicate the positive influence of GM-CSF on neutrophil recovery and hospital stay in patients receiving ABMT for a variety of clinical indications.

Summary form only given. This paper describes the design of a high speed motion estimator using the 2-D log search algorithm. The architecture consists of 5 simple processing elements (PE) where each PE is capable of computing the sum-of-absolute-difference (SAD) to exploit the parallelism. For each step in the 2-D log search procedure, the 5 SADs of the 5 search points are computed in parallel. The design is implemented using Verilog and synthesized using Synopsys. Simulations show that the architecture is able to generate the motion vector for each 16/spl times/16 macroblock in 14.58 /spl mu/s for 3-step log search, and 24.30 /spl mu/s for 5-step log search. The architecture is thus well suited for encoding MPEG2 video up to MP@ML.

8035 Background: There remains a lack of prospective data studying ABVD or Stanford V in the modern era in advanced-stage elderly HL (≥60 years). Methods: We analyzed outcomes and tolerability of e...

e18517 Background: For PMBCL the role of radiation therapy (RT) following rituximab (R)-based regimens is unknown. The purpose of this study was to evaluate the outcome of PMBCL according to treatm...

8064 Background: Combined modality therapy is the standard of care for non-bulky Stage I-II HL. Currently, brief CT +30 Gy involved field (IF) radiotherapy (RT) is associated with a high cure rate....

8032 Background: sALCL is a CD30-expressing malignancy comprising ~2-3% of all NHL cases. Brentuximab vedotin consists of an anti-CD30 antibody conjugated by a plasma-stable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). Brentuximab vedotin selectively induces apoptotic death of CD30+ cells by binding, internalizing, and releasing MMAE. Methods: A phase II, single-arm, multicenter study evaluated the efficacy and safety of brentuximab vedotin in patients (pts) with relapsed or refractory sALCL. Pts received brentuximab vedotin 1.8 mg/kg q3 weeks (wks) as a 30‐minute outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per an independent review facility (IRF) according to Cheson 2007. Results: 58 pts were enrolled; 57% were male, median age was 52 yrs (range 14–76 yrs). 72% of pts had ALK negative sALCL. Pts had received a median of 2 (range 1–6) prior systemic therapies. 62% of pts had primary refractory disease, 50% were refra...

Summary form only given. A compact pulse transformer has been developed to operate at /spl sim/1 Hz, producing a 100 kV, 250 ns pulse. The output pulse has a /spl plusmn/1% flat top for 120 ns. This pulse is coupled to an electron beam diode which uses a ferroelectric ceramic disk as the source of a high-current-density electron beam. A portion of the pulse (/spl sim/2 kV) is applied across the ferroelectric, causing a rapid change in the polarization state. This change results in the emission of a high-density electron cloud into an accelerating diode gap. The accelerating pulse is applied across the diode gap and the electron beam is extracted into a cylindrical drift tube. The diode gap is adjusted between 1-10 mm and the anode potential is varied from 0-500 V. The emitted current is measured as a function of these parameters. Current densities of 70 A/cm/sup 2/ have been measured. The Child-Langmuir current density, for 500 V applied across a 4 mm gap, is 0.2 A/cm/sup 2/.

Previously, we reported that in cord blood there is a population of very dense, surface area-depleted red blood cells (RBC). We hypothesized that oxidative damage might account for the generation of this cell population because Hb F is known to be mildly unstable in vitro. Accordingly, we examined density-separated subpopulations of neonatal red cells searching for evidence of oxidant injury to Hb in vivo. Cord or adult RBC were separated into populations of varying density and an increased amount of membrane-associated globin was found in the densest fraction of cord RBC. Solubilized ghosts from each fraction were analyzed by thiol-disulfide exchange chromatography for the presence of oxidized Hb and spectrophotometrically for the presence of membrane-bound hemichrome. About four times more oxidized Hb was found in unseparated cord RBC than in adult RBC. This difference was most evident in the densest 10-15% RBC subfractions. Membrane-bound hemichrome levels in cord cells were twice those found in adult cells. We found that in cord membrane skeletons there was 2.5 to 9 times as much globin in the dense fraction as compared to the light fraction. Membrane skeletons from dense and light adult RBC differed little from one another. We postulate that membrane (and perhaps membrane skeleton)-associated oxidized Hb is a marker for more generalized oxidative damage, which may create the population of unusually dense cells found in cord blood and ultimately shorten their life span.

The aim of the present work was to understand the pathophysiology of the severe human thalassemias as represented by beta-thalassemia intermedia and hemoglobin (Hb) H (alpha-thalassemia) disease. We have previously shown that the material properties of the red blood cell (RBC) and its membrane differ in severe alpha- and beta-thalassemia, and we now show that this difference is probably caused by accumulation of alpha-globin chains at the cytoskeleton in beta-thalassemia, whereas beta-globin chains are associated with the cytoskeleton in alpha-thalassemia. In both alpha- and beta-thalassemia, some of these globin chains have become oxidized as evidenced by loss of the free thiols. Furthermore, there is similar evidence of oxidation of protein 4.1 in beta-thalassemia, whereas beta-spectrin appears to be subject to oxidation in alpha-thalassemia. These observations support the idea that the association of partly oxidized globin chains with the cytoskeleton results in oxidation of adjacent skeletal proteins. The abnormality of protein 4.1 in beta-thalassemia is consistent with a prior observation, and is also in accord with the known importance of protein 4.1 in maintenance of membrane stability, a property that is abnormal in beta-thalassemic membranes.

In severe human beta-thalassemia, the pathophysiology relates to accumulation of excess alpha-globin chains at the membrane. One hypothesis is that membrane-associated alpha-globin by virtue of it's iron or hemichromes produces oxidation of adjacent membrane proteins. The availability of a mouse model of severe beta-thalassemia, as well as a transgenic (thalassemic-sickle) mouse that expresses 12% of human beta s-chain, has allowed us to study the effect of graded accumulation of alpha-chains at the red blood cell (RBC) membrane on the clinical status of the animal and on the material properties of its RBCs. Proteins from control, beta-thalassemic, and transgenic mouse RBC membranes were analyzed for evidence of oxidation, as measured by thiol-disulfide exchange chromatography, which detects intramolecular sulfhydryl oxidation. Ratios of oxidized globin to protein 7 were calculated and increased amounts were seen in thalassemic mice as compared with control mice and transgenic mice. Furthermore, there were increased amounts of thiol-free protein 4.1 in the thalassemic mice, compared with very small amounts in the control mice and intermediate amounts in the transgenic mice. Membrane mechanical stability as assessed by ektacytometry showed that the thalassemic mouse RBCs were markedly unstable. Transgenic mouse RBCs showed intermediate levels of membrane instability compared with the controls. We propose that this oxidized globin, in conjunction with oxidized protein 4.1, accounts (at least in part) for membrane instability. A 12% increase in beta s-globin chain synthesis (by decreasing excess globin available) confers considerable protection against both oxidative damage and the consequent membrane instability.

11063 Background: Dacetuzumab (SGN-40) is a humanized IgG1 monoclonal antibody that binds to CD40, mediates effector cell functions, and activates downstream apoptosis signaling pathways. Dacetuzumab has shown single-agent activity in relapsed/refractory DLBCL in phase I and phase II trials, with multiple objective responses and 1/3 of patients demonstrating tumor shrinkage, defined as a decrease in tumor volume (SPD) of at least 10%. We previously reported a 14-gene signature (ASH 2008 #1593) that was strongly associated with dacetuzumab sensitivity in DLBCL cell lines. Here, we report an initial evaluation of the gene signature as a classifier of patients likely to demonstrate tumor shrinkage after dacetuzumab therapy. Methods: The original 14 microarray probes were chosen for high correlation with in vitro dacetuzumab sensitivity (IC25) in 31 NHL cell line models. Matching qRT-PCR probes were developed and confirmed to correlate with the microarray probes in paired cell line samples. In this retrospective analysis, archived paraffin blocks from a 26 patient subset of the phase I and II trials, with a diagnosis of DLBCL and available tumor measurements, were assayed by qRT-PCR. Results: Overall, 42% of patients (11/26) exhibited decreased SPD of at least 10%. Of those who were marker +, 10 out of 13 (78%) had 10% or better decreases in SPD, whereas only 1 of 13 patients who were marker - demonstrated tumor shrinkage (8%). The overall accuracy for predicting tumor shrinkage was 85% (one-sided P=0.002, by permutation test). Among the 14 genes contributing to the multivariate signature, CD22 and VNN2 were the most strongly down-regulated in specimens from patients without at least a 10% decrease in SPD (P=0.14 and P=0.10, respectively), while IGF1R and CTSC were the most strongly up-regulated (P=0.05 and P=0.08, respectively). Conclusions: A 14-gene signature appears to predict tumor shrinkage in DLBCL patients receiving dacetuzumab in single-agent clinical trials (P=0.002). A larger clinical data set will be analyzed to further evaluate the correlation of this gene signature with objective clinical response rates.. [Table: see text]

8014 Background: We conducted a prospective randomized trial from 1980–88 comparing IFRT plus VBM (vinblastine, bleomycin, methotrexate) chemotherapy to extended field radiation (EFRT) in patients with favorable stage I-IIIA disease to limit radiation exposure and define an effective treatment regimen that preserved fertility and did not increase the risk of leukemia. Methods: Patients (pt) with favorable, laparotomy-staged disease were defined as those with no bulky mediastinal disease, no or minimal abdominal disease ( No significant financial relationships to disclose.

7503 Background: Because mantle cell lymphoma (MCL) has a continuous relapse pattern with current treatments, we designed a study to determine the safety and efficacy of the anti-CD20 radio-immunoconjugate,90Y-ibritumomab tiuxetan (90Y-RIT), after R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) induction. Methods: Patients (pt) with untreated stage II-IV MCL (CD20+, cyclin D1+) ≥18 yr were eligible if they had measurable/evaluable disease, adequate organ function (WBC >2,500/μl; platelets >100,000/μl unless marrow-positive) and gave informed consent. At 4–8 weeks after 4 cycles of R-CHOP, stable and responding pt meeting standard marrow and hematologic criteria received 0.4 mCi/kg 90Y-ibritumomab tiuxetan. Objectives were to evaluate response and toxicity after R-CHOP and 90Y-RIT with a primary endpoint of time to treatment failure (TTF). Results: 56 of 57 accrued patients are eligible pending central pathology review. Characteristics included 73% male, median age 60 (33–83) yrs, 91% stage III/IV, 64% >1 extranodal site, 75% marrow-positive. IPI was 0–2 in 50%, 3–5 in 43% and unknown in 7%. After 90Y-RIT 53% had grade 3/4 neutropenia with no febrile neutropenia and 45% had grade 3/4 thrombocytopenia with recovery at 12 weeks in 19/20 pt. 50 pt are evaluable for response after R-CHOP and 44 pt after 90Y-RIT. Best response after R-CHOP (n = 50) was: CR/CRu 14% (n = 7), PR 58% (n = 29), SD 26% (n = 13), PD 2% (n = 1). After 90Y-RIT, responses improved in 15 of 37 pt with 90Y RIT after 4 cycles of R-CHOP in untreated MCL is safe and improves the number and quality of responses. Further follow-up is needed to determine TTF. [Table: see text]